GABAA receptors as targets for treating affective and cognitive symptoms of depression - PubMed (original) (raw)

Review

GABAA receptors as targets for treating affective and cognitive symptoms of depression

Bernhard Luscher et al. Trends Pharmacol Sci. 2023 Sep.

Abstract

In the past 20 years, our understanding of the pathophysiology of depression has evolved from a focus on an imbalance of monoaminergic neurotransmitters to a multifactorial picture including an improved understanding of the role of glutamatergic excitatory and GABAergic inhibitory neurotransmission. FDA-approved treatments targeting the glutamatergic [esketamine for major depressive disorder (MDD)] and GABAergic (brexanolone for peripartum depression) systems have become available. This review focuses on the GABAA receptor (GABAAR) system as a target for novel antidepressants and discusses the mechanisms by which modulation of δ-containing GABAARs with neuroactive steroids (NASs) or of α5-containing GABAARs results in antidepressant or antidepressant-like actions and discusses clinical data on NASs. Moreover, a potential mechanism by which α5-GABAAR-positive allosteric modulators (PAMs) may improve cognitive deficits in depression is presented.

Keywords: GABA(A) receptor; Gabra5; Gabrd; chronic stress; cognition; depression; emotion; neurosteroids.

Copyright © 2023 Elsevier Ltd. All rights reserved.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests J.L.M. serves on the Scientific Advisory Board and has a sponsored research agreement with SAGE Therapeutics. U.R. is Scientific Advisor to Damona Pharmaceuticals. E.S. is the cofounder and chief scientific officer of DAMONA Pharmaceuticals. He is listed on patents for molecules modulating GABAergic functions, which are licensed to DAMONA Pharmaceuticals. B.L. has no conflict of interest (and current funding) to report.

Figures

Fig. 1:

Fig. 1:. Cortical GABAergic microcircuit controlling stress vulnerability and resilience relevant for depressive disorders and antidepressant drug action.

The large majority of SST cells (i.e. >70%) represent Martinotti cells that preferentially innervate the distal apical tufts of pyramidal neurons (PN) were in cortical Layer 1 [105]. PV-positive interneurons preferentially innervate the somata, proximal dendrites, and axon initial segments of PNs and thereby exert powerful control over action potential firing of these neurons. VIP cells preferentially inhibit SST cells, which causes disinhibition of PNs. PV and SST cells also innervate each other. In particular, inhibition of PV cells by a subset of SST cells in layer 4 that are distinct from Martinotti cells, produces disinhibition of PNs [105]. The distinctive functional properties of SST cells suggest they exert a neuroprotective role. First, the activity of SST neurons, but not PV neurons in the prefrontal cortex scales with the strength of excitatory synaptic inputs from the basolateral amygdala (BLA) (1). Second, GABAergic inputs to PN dendrites buffer the temporal and spatial spread of NMDA receptor-mediated Ca2+ entry at adjacent glutamatergic synapses on dendritic spines [106] (2). Third, GABAergic inhibition of dendritic spines by SST neurons is principally mediated by postsynaptic α5-GABAARs, presumably composed of 2α5, 2β and 1γ2 subunit [92] (3). Fourth, genetically increasing the excitability of SST cells mimics the behavioral effects of antidepressant drug treatment [7] including stress resilience [8]. Lastly, SST neurons in the mPFC are direct targets also of excitatory inputs from the vHPC [71] (4).

Fig. 2:

Fig. 2:. Pathological and therapeutic roles of neurosteroids in the BLA in depression.

PV interneurons in the BLA are critical for governing the activity of BLA principal neurons and network states driving behavioral states. PV interneurons in the BLA uniquely express the δ-GABAARs. Chronic stress has been shown to decrease the expression of δ-GABAARs in the BLA, which is the primary site of action for neurosteroids, suggesting that neurosteroid signaling may be impaired in the BLA following chronic stress exposure. Consistent with deficits in neurosteroid signaling, chronic stress is associated with a reduction in the expression of 5α-reductase (Srd5a1/2), a key enzyme in neurosteroidogenesis. Further, the endogenous levels of allopregnanolone are decreased in the BLA following chronic stress. Given that chronic stress is a major risk factor for MDD and the evidence that neurosteroids exert robust anxiolytic and antidepressant effects, impaired endogenous neurosteroid signaling may contribute to deficits in emotional processing and MDD. Impaired endogenous neurosteroidogenesis related to MDD may also help explain the therapeutic efficacy of exogenous NAS treatment for restoring the healthy behavioral state and treating MDD.

Fig 3:

Fig 3:. Chemical formulas of neuroactive steroids and modulators of α5-GABAARs.

Left: Formulas of neuroactive steroids used in clinical studies of depressive disorders. Right: Formulas of modulators of the α5-GABAAR used in preclinical studies.

Fig. 4:

Fig. 4:. Model of a microcircuit relevant for cognition in depression and restoration of cognitive deficits with an α5-PAM.

A. Procognitive effects of α5-PAMs in depression through improved signal-to-noise ratio at the cellular level. Left panel: Dendrite-targeting somatostatin (SST)-positive interneurons inhibit pyramidal neurons via α5-GABAARs, resulting in a sparse baseline activity of the pyramidal neurons. This inhibition is mediated by α5-GABAAR (short green “B” arrows). Stronger excitatory signals are not inhibited by these SST interneurons (long green “S” arrows). This results in a high signal-to-noise ratio (SNR) which is required for optimal cognitive function. Middle panel: In depression, the excitatory activity of the pyramidal neurons is increased, while the inhibitory activity of the SST interneurons is decreased. The result is that the baseline activity of the pyramidal neurons is not as efficiently inhibited as in the healthy brain so that more baseline signals result in activation of the pyramidal neurons (B) and, while there is no change in the transmission of stronger excitatory signals through the pyramidal neurons (S), this results in a lower signal-to-noise-ratio with poor coding of information and cognitive deficits. Right panel: Administration of an α5-PAM strengthens the inhibition of the pyramidal neurons by the SST interneurons, so that incoming baseline activity is inhibited, as in the healthy condition, and not propagated, while stronger excitatory signals are propagated through the pyramidal neurons, resulting in restoration of a high signal-to-noise-ratio and normalized cognitive function. B. Cognition as a function of the activity of α5-GABAARs. There is an optimal level of activity of the α5-GABAAR system for cognitive performance. Both a lower and a higher activity result in cognitive impairments. In depression, the activity of the α5-GABAAR system is reduced, resulting in cognitive impairment. Administration of an α5-PAM increases the activity level of the α5-GABAAR system and thus restores learning and memory (L&M) performance.

Fig. 5 (KEY FIGURE):

Fig. 5 (KEY FIGURE):. Proposed mechanisms of α5-PAMs and α5-NAMs for normalization of defects in GABAergic and glutamatergic deficits in stress-associated psychiatric conditions.

Behavioral stress involves a rapid increase in glutamatergic synaptic transmission and acts over time to result in defects of GABAergic inhibition as evidenced by reduced expression of glutamic acid decarboxylase (GAD) and of the vesicular GABA transporter [107], reduced SST neuron function [5] [108], and reduced NAS synthesis [109]. Chronic stress and deficits in GABAergic synaptic inhibition are followed by homeostatic-like downregulation of AMPA and NMDA-type glutamate receptors and of the vesicular transporter for glutamate [101] [107]. Potentiation of GABAergic inhibition by PAMs appears to allow for a gradual recovery of glutamate receptor expression and eventually also of GABAergic transmission. Very different from GABAAR PAMs, acute doses of α5-GABAAR NAMs lead to a rapid and transient decrease of dendritic GABAergic inhibition, a corresponding increase in glutamatergic transmission and activity-induced and NMDAR-mediated plasticity including especially at α5-GABAAR expressing dendritic spines [92]. This mechanism of α5-GABAAR NAMs is reminiscent of the rapid antidepressant mechanism of subanesthetic ketamine, which involves selective and transient inhibition of PV and SST GABAergic interneurons followed by disinhibition of glutamatergic neurons and LTP-like NMDA receptor mediated potentiation of both GABAergic and glutamatergic synapses on pyramidal cells, lasting for days ([9] and reviewed in [10]).

Similar articles

Cited by

References

    1. Malhi GS and Mann JJ (2018) Depression. Lancet 392 (10161), 2299–2312. - PubMed
    1. Delgado PL (2000) Depression: the case for a monoamine deficiency. J Clin Psychiatry 61 Suppl 6, 7–11. - PubMed
    1. Engin E et al. (2018) An Emerging Circuit Pharmacology of GABA(A) Receptors. Trends Pharmacol Sci 39 (8), 710–732. - PMC - PubMed
    1. Prevot TD et al. (2019) Novel Benzodiazepine-Like Ligands with Various Anxiolytic, Antidepressant, or Pro-Cognitive Profiles. Mol Neuropsychiatry 5 (2), 84–97. - PMC - PubMed
    1. Luscher B et al. (2011) The GABAergic deficit hypothesis of major depressive disorder. Mol Psychiatry 16 (4), 383–406. - PMC - PubMed

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources